ABSTRACT Dravet Syndrome (DS) is a devastating childhood neuropsychiatric disorder caused by de novo, heterozygous loss-of- function mutations in the brain type-I voltage-gated Na channel Nav1.1. We have developed a mouse genetic model with all the features of DS, including susceptibility to thermally induced seizures and spontaneous seizures, ataxia, circadian rhythm and sleep disorders, cognitive deficit, autistic-like behaviors, and premature death. All these effects are correlated with loss of Na currents and excitability of GABAergic interneurons, which causes imbalance of excitation vs. inhibition in neural circuits. Mutation of Nav1.1 channels specifically in forebrain GABAergic interneurons by the Cre-Lox method is sufficient to cause the major DS symptoms, confirming that DS is caused by loss of Nav1.1 channels in inhibitory neurons. Remarkably, cognitive deficit and autistic-like behaviors of DS mice can be rescued by treatment with a low dose of the GABA-A receptor co-activator clonazepam, demonstrating that these life-changing co-morbidities are caused by the mutation of Nav1.1 channels rather than by neuronal damage from recurrent seizures. Our central questions now are: (i) Which inhibitory neuron types are involved in epilepsy and cognitive deficits? (ii) When does mutation of Nav1.1 in these neurons cause DS? (iii) Where are vulnerable interneurons located? (iv) Can novel combinations of drugs prevent both seizures and cognitive deficit in DS mice? (v) Will drug combinations retain efficacy in chronic use without tolerance? In order to address these crucial questions, we will use cell-specific gene deletion with the Cre-Lox method, timed gene deletion with tamoxifen-induced Cre recombinase, and local deletion by stereotaxic injection of virally expressed Cre to further dissect the interneuron types, developmental timing, and brain locations in which mutation of Nav1.1 causes epilepsy in DS. Electrophysiological studies will reveal deficits in cellular excitability that cause DS. We will develop optogenetic approaches to induce and rescue epilepsy in DS mice by local expression of Arch, Channelrhodopsin, and new generations of optogenetic probes in specific classes of inhibitory neurons. We will assess the potential dysfunction of the `dentate gate' in generating seizures in DS mice. In order to understand cognitive deficit in DS, we will use a similar gene deletion strategy to determine the interneuron types, developmental timing, and brain location in which deletion of Nav1.1 channels cause cognitive deficit, and we will measure induction and rescue of cognitive deficit with the context-dependent fear conditioning and Barnes maze tests. Electrophysiological studies in brain slices and intact mice will identify the deficits in cellular excitability and circuit function that cause cognitive deficit in DS mice. Based on our emerging understanding of epilepsy and cognitive deficit in DS mice, we will develop novel therapeutic approaches combining cannabidiol for treatment of seizures with a low dose of a benzodiazepine such as clonazepam, clobazam, or a next-generation drug to rescue cognitive deficits. We will determine the physiological mechanisms responsible for therapeutic effects of optimal drug combinations, and we will develop long-term treatment methods to assess and prevent development of tolerance. Overall, our results will give crucial new insights into the pathophysiology of DS and provide novel, but practical, approaches to therapy of this disastrous disease.